Epigenetic controls play a role in a variety of biological phenomena including cell differentiation, gene inactivation and silencing of foreign DNA. Rather than serving simply an organizational role for DNA packing, chromatin structure plays important roles in the epigenetic control of gene expression. Chromatin structure influences nearly all DNA-related processes, including replication, repair, recombination and transcription (Kornberg et al., 1999, Cell 98:285-94; Shilatifard, 2006, Ann. Rev. Biochem. 75:243-69; Jenuwein and Allis, 2001, Science 293:1074-80). The basic unit of chromatin is the nucleosome. A nucleosome consists of 147 base pairs of DNA wrapped around an octamer of histones that is made up of two H2A-H2B dimers and a single H3-H4 tetramer (Luger et al., 1997, Nature 389:251-60). Histones are highly conserved proteins from yeast to humans. The structure of chromatin is altered by the post-translational modification of histones (Kornberg et al., 1999, Cell 98:285-94; Shilatifard, 2006, Annu. Rev. Biochem. 75:243-69; Jenuwein & Allis, 2001, Science 293:1074-80), by interactions with other proteins such as ATP-dependent chromatin-remodeling complexes, or by replacement of core histones with histone variants (Mito et al., 2007, Science 315:1408-11; Polo, 2006, Cell 127:481-93; Lacoste & Almouzni, 2008, Nat. Cell Biol. 10:7-9). Post-translational covalent modifications of histones are known to include serine and threonine phosphorylation, lysine acetylation, lysine and arginine methylation and ubiquitination (Bhaumik et al., 2007, Nat. Struct. Mol. Biol. 14:1008-16; Berger, 2002, Curr. Opin. Genet. Dev. 12:142-48).
When environmental conditions such as nutrient depletion compromise survival, the budding yeast Saccharomyces cerevisiae induces and completes a differentiation program called sporulation. The first step consists of meiosis, which generates genetic diversity within the eventual haploid cells. The post-meiotic maturation stage reinforces protective barriers, such as the spore wall, against deleterious external conditions. The sporulation differentiation program involves many chromatin-related events, including execution of a precise transcription program involving more than one thousand genes. In later stages of yeast sporulation, the spore nucleus becomes highly compacted, sharing certain characteristics with the metazoan male gamete, the spermatozoon. In addition, yeast sporulation follows a sequence of events similar to that of higher eukaryotic spermatogenesis. In both cases, genetic information is recombined during meiosis, and then compacted and stored in a unique chromatin structure (that is, compared to vegetative or somatic cells) in haploid, highly differentiated cells. Remarkably, spores germinate to restore a fully functional vegetative cell, just as gametes generate an entire new somatic organism.
There is a need in the art to elucidate the epigenetic commonalities between yeast sporulation and higher eukaryotic gametogenesis as a means of studying mammalian gametogenesis. Moreover, there exists a need in the art to identify epigenetic markers associated with mammalian infertility. The present invention satisfies these needs.